This invention relates to novel compositions of matter containing optically pure (+) cetirizine. These compositions possess potent activity in treating seasonal and perennial allergic rhinitis, the symptoms of allergic asthma, chronic idiopathic urticaria, some types of physical urticaria, and other disorders including those that would benefit from an inhibitory action on eosinophil function. (+) Cetirizine inhibits eosinophil chemotaxis and function and the generation of cytotoxic mediators by blood platelets, providing therapy in immunologically-induced asthma with particular utility in the late phase of the disease episode. Optically pure (+) cetirizine provides this treatment while avoiding adverse effects, including, but not limited to, sedation and somnolence, headache, gastrointestinal disturbance, anticholinergic effects, dizziness, cardiac arrhythmias and other cardiovascular effects which are associated with the administration of the racemic mixture of cetirizine. Also disclosed are methods for treating the above described conditions in a human while avoiding the adverse effects that are associated with the racemic mixture of cetirizine by administering the (+) isomer of cetirizine to said human.
The active compound of these compositions and methods is an optical isomer of cetirizine, the preparation of which is described in U.S. Pat. No. 4,525,358 (Baltes et al.). The medicinal chemistry of cetirizine is described by Campoli-Richards et al., [Drugs 40, 762-781 (1990)], Snyder and Snowman [Allergy 59 II, 4-8 (1987)], and Rihoux and Dupont [pu Annals of Allergy 59, 235-238 (1987)]. Chemically, the active compound is the (+) isomer of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl) ethoxyacetic acid, hereinafter referred to as cetirizine.
(+) Cetirizine, which is the subject of the present invention, is not presently commercially available; only the 1:1 racemic mixture is commercially available as its dihydrochloride salt.
Many organic compounds exist in optically active forms, i.e.. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen. The synthesis of (+) cetirizine and (-) cetirizine are described in British application 2,225,321, but no pharmacology of individual enantiomers is reported.
The racemic mixture of cetirizine is presently used primarily in seasonal and perennial allergic rhinitis. The symptomatology of immediate-type allergic diseases, including allergic rhinitis, presumably results from the antigen-induced release of various pharmacologically active substances from mast cells, and from basophilic leukocytes. The substances thus released from these cells, and possibly others as well, are referred to as primary mediators of anaphylaxis and include, among others, histamine. The acute seasonal form of allergic rhinitis, hay fever, and perennial allergic rhinitis are characterized by sneezing, rhinorrhea, nasal congestion, pruritus, conjunctivitis and pharyngitis. In acute seasonal rhinitis, the nose, roof of the mouth, eyes and pharynx often itch, and lacrimation, sneezing and clear, watery nasal discharge follow the pruritus. Additionally, frontal headaches, irritability, anorexia, depression and insomnia may occur. In perennial rhinitis, chronic nasal obstruction is often prominent and may extend to eustachian tube obstruction. For most patients, topical corticosteriods, some aerosol vasoconstrictor agents, and long acting antihistamine agents provide significant relief of symptoms. The action of cetirizine on non-immunologically (non IgE) mediated hypersensitivity reactions has been less clear although there are some suggestions of activity in the treatment of exercise induced asthma, cold urticaria, and non-specific bronchial hyperreactivity.
Racemic cetirizine dihydrocholoride is an orally active, potent, long acting peripheral histamine H.sub.1 receptor antagonist. The compound is one of the second generation of H.sub.1 histamine receptor antagonists which generally offer some significant advantages beyond the first generation compounds. The advantages include (1) less sedation, (2) little anticholinergic activity and (3) longer duration, which improves patient compliance. In addition to being competitive inhibitors of histamine at the end organ site, second generation H.sub.1 histamine inhibitors appear to have other anti-allergic pharmacologic mechanisms which have led to their use in bronchial asthma, as well as in seasonal and perennial rhinitis and the chronic urticarias.
Experiments ex vivo suggest that racemic cetirizine does not significantly penetrate the blood brain barrier. It has been suggested therefore that cetirizine's ability to provide a reduced incidence of sedative side effects may result in part from its receptor selectivity and in part from its relative exclusion from the CNS. Other experiments have suggested that cetirizine does not inhibit mast cell activation but rather that it antagonizes the action of histamine once released from the mast cell following antigen or chemical stimulation. There are also reports that racemic cetirizine inhibits the degranulation of human basophils induced by anti IgE. Cetirizine has been shown to inhibit the chemotaxis of eosinophils to the tissues where they would otherwise contribute to the pathogenesis of asthma.
Cetirizine is rapidly absorbed upon oral administration and although food may slightly reduce the rate of absorption, the extent is not affected. The compound is bound to plasma proteins and peak cetirizine concentrations in the brain are less than 10% that of the plasma concentration. Cetirizine is excreted in the urine largely as unchanged drug and the elimination half-life is roughly 7 to 10 hours.
The racemic mixture of cetirizine may be useful in treating other disorders such as allergic pulmonary disease and particularly in treating the symptoms of allergic bronchial asthma. Patients who suffer from allergic bronchial asthma develop such clinical symptoms as wheezing and dyspnea after exposure to allergens, environmental irritants, viral infections, cold air and exercise. Many of the symptoms result from smooth muscle contraction and vascular dilatation, which, in turn, result from mediator release when the antigen reacts with the IgE antibody on the surface of a mast cell or basophil. This serves as a basis for the use of histamine H.sub.1 antagonists.
In addition, racemic cetirizine may be useful for treating chronic idiopathic urticaria and some types of physical urticaria. Urticaria is characterized by local wheals and erythema in the dermis; acute urticaria is essentially an anaphylaxis that is limited to the skin and subcutaneous tissues. The condition may arise from food allergy, drug allergy, insect sting, or the like, and is distinct from chronic or idiopathic urticaria which may last for several weeks and can only rarely be associated with a specific cause. Because these urticarias appear in many cases to be IgE antibody mediated, many of the symptoms may be treated with a histamine H.sub.1 receptor antagonist such as cetirizine. The direct inhibition of eosinophil chemotaxis by cetirizine may also provide therapy to the late phase of allergic episodes in disorders such as allergic asthma, allergic rhinitis, and in other conditions characterized by eosinophilia.
Many of the second generation histamine H.sub.1 receptor antagonists offer advantages over the first generation of histamine antagonists in that there is reduced sedation and anticholinergic activity. Nonetheless, some adverse effects remain, including, but not limited to, some incidence of sedation and somnolence; cardiovascular effects including arrhythmias; headache; gastrointestinal disturbances; dizziness and nausea. The racemic mixture of cetirizine has been found to cause many of these adverse effects, including sedation and somnolence. Thus, it would be particularly desirable to find a compound with the advantages of the racemic mixture of cetirizine which would not have the aforementioned disadvantages.